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Bicyclo [2.2.1] acid GPR120 modulators

a technology of bicyclo[2.2.1] and gpr120, which is applied in the field of bicyclo2 . 2 . 1 compounds, can solve the problems of micro- and macrovascular complications and morbidity, and achieve the effects of improving the gpr120 activity and gpr120 activity

Active Publication Date: 2016-12-13
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]The compounds of the invention may be used in the treatment of multiple diseases or disorders associated with GPR120, such as diabetes and related conditions, microvascular complications associated with diabetes, the macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, disorders of glucose metabolism, obesity and other maladies.
[0009]The compounds of the invention may be used in therapy.
[0010]The compounds of the invention may be used for the manufacture of a medicament for the treatment of multiple diseases or disorders associated with GPR120.
[0007]The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.
[0012]Other features and advantages of the invention will be apparent from the following detailed description and claims.

Problems solved by technology

Diabetes mellitus is a progressively debilitating disorder of epidemic proportions leading to various micro- and macrovascular complications and morbidity.

Method used

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  • Bicyclo [2.2.1] acid GPR120 modulators
  • Bicyclo [2.2.1] acid GPR120 modulators
  • Bicyclo [2.2.1] acid GPR120 modulators

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0350]To a 0° C. suspension of methyl 4-(4-hydroxybicyclo[2.2.1]heptan-1-yl) butanoate (10 mg, 0.047 mmol), 2,6-di-tert-butylpyridine (0.016 mL, 0.071 mmol), and AgOTf (13 mg, 0.052 mmol) in CH2Cl2 (0.5 mL) was added 5-(bromomethyl)-1-(4-chlorophenyl)-3-methyl-1H-pyrazole (16.14 mg, 0.057 mmol); a yellow precipitate formed within a few minutes. The reaction was slowly warmed up to rt and stirred at RT overnight. The reaction was diluted with CH2Cl2 and filtered through a plug of CELITE®. The filtrate was concentrated in vacuo. The residue was taken up in THF (1 mL) and water (0.5 mL), and LiOH.H2O (10 mg, 0.24 mmol) was added. The reaction was stirred at rt overnight and diluted with EtOAc (30 mL) and H2O (20 mL). The aqueous layer was washed with EtOAc (2×10 mL). The organic layer was extracted with H2O (3×20 mL). The combined aqueous extracts were adjusted with 1 N aq. HCl to pH ˜3 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (10 mL), dr...

example 68

[0364]The title compound was prepared using a procedure analogous to Example 1 except that methyl 4-(4-hydroxybicyclo[2.2.1]heptan-1-yl)butanoate was replaced with ethyl 4-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-2-methylbutanoate. LCMS, [M−H]+=393.1. 1H NMR (500 MHz, CDCl3) δ 7.55 (dd, J=7.4, 1.4 Hz, 1H), 7.34-7.29 (m, 2H), 7.25-7.20 (m, 1H), 7.17-7.12 (m, 1H), 7.10-7.05 (m, 1H), 6.97-6.93 (m, 2H), 6.88 (dd, J=8.1, 1.0 Hz, 1H), 4.58 (s, 2H), 1.86-1.77 (m, 2H), 1.69-1.49 (m, 7H), 1.47-1.39 (m, 6H), 1.19 (d, J=6.9 Hz, 3H). HPLC-1: RT=13.2 min, purity=92.8%; HPLC-2: RT=11.1 min, purity=100%.

example 69

3-Methyl-4-(4-(3-phenoxybenzyloxy)bicyclo[2.2.1]heptan-1-yl)butanoic acid

[0365]

[0366]The title compound was synthesized similarly as for Example 68 through the following sequence: (1) reaction of 4-methoxybicyclo[2.2.1]heptane-1-carbaldehyde with the anion of (methoxymethyl)triphenylphosphonium chloride to afford the corresponding ester; (2) TMSI treatment to give the alcohol as in 68E; (3) AgOTf-mediated alkylation of the alcohol as in Example 1H; (4) LiOH hydrolysis of the ethyl ester as in Example 1H; (5) one-carbon elongation of the resulting acid using the Arndt-Eistert reaction sequence provided the title compound. LCMS, [M−H]+=393.1. 1H NMR (500 MHz, CDCl3) δ 7.57 (dd, J=7.55, 1.51 Hz, 1H), 7.36-7.31 (m, 2H), 7.24 (td, J=7.84, 1.72 Hz, 1H), 7.16 (td, J=7.48, 1.09 Hz, 1H), 7.10-7.06 (m, 1H), 6.99-6.95 (m, 2H), 6.90 (dd, J=8.1, 1.0 Hz, 1H), 4.59 (s, 2H), 2.36 (dd, J=15.2, 5.97 Hz, 1H), 2.18 (dd, J=15.2, 8.0 Hz, 1H), 2.1-2.0 (m, 1H), 1.87-1.78 (m, 2H), 1.69-1.56 (m, 4H), 1.54-1....

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Abstract

The present invention provides compounds of Formula (I): (I) or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR120 G protein-coupled receptor modulators which may be used as medicaments.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 782,469, filed Mar. 14, 2013; the entire content of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention provides novel bicyclo[2.2.1] compounds, and their analogues thereof, which are GPR120 G protein-coupled receptor modulators, compositions containing them, and methods of using them, for example, for the treatment of diabetes and related conditions.BACKGROUND OF THE INVENTION[0003]Diabetes mellitus is a progressively debilitating disorder of epidemic proportions leading to various micro- and macrovascular complications and morbidity. The most common type of diabetes, type 2 diabetes, is characterized by increasing insulin resistance associated with inadequate insulin secretion after a period of compensatory hyperinsulinemia. Polyunsaturated fatty acids (PUFAs) such as omega-3 fatty acids are known to improve sensitivity t...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/415C07D333/56A61K45/06A61K31/343A61K31/381A61K31/397C07C59/13C07C69/675C07C69/708C07C69/732C07C69/734C07C69/736C07C69/757C07C69/76C07C43/192C07C43/196C07C47/277C07C59/72C07C62/34C07C311/51C07C235/26C07C237/22A61K31/192C07C59/215C07C205/34C07C323/19C07D307/79C07D333/16C07D333/28C07D271/06C07D239/38A61K31/505C07D231/12A61K31/4245C07D205/04
CPCA61K31/192A61K31/343A61K31/381A61K31/397A61K31/415A61K31/4245A61K31/505A61K45/06C07C43/192C07C43/196C07C47/277C07C59/215C07C59/72C07C62/34C07C69/675C07C59/13C07C69/708C07C69/732C07C69/734C07C69/736C07C69/757C07C69/76C07C205/34C07C235/26C07C237/22C07C311/51C07C323/19C07D205/04C07D231/12C07D239/38C07D271/06C07D307/79C07D333/16C07D333/28C07D333/56C07C2101/02C07C2102/08C07C2102/42C07C2601/02C07C2602/08C07C2602/42A61P1/16A61P13/12A61P17/02A61P25/00A61P27/02A61P3/00A61P3/04A61P3/06A61P5/50A61P9/00A61P9/10A61P9/12A61P3/10
Inventor SHI, YANCHENG, PETER T. W.WANG, YINGWU, SHUNG C.ZHANG, HAO
Owner BRISTOL MYERS SQUIBB CO
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